Success of Herceptin to breast cancer (see, non-patent document 1) and Rituxan (non-patent document 2) to malignant lymphoma B shows that an antibody is effective as a therapeutic agent to a cancer. Certain antibodies exhibit an ADCC effect (non-patent document 3) and/or a CDC effect (non-patent document 4) by forming a complex with an antigen molecule existing on the cell membrane and the effects kill a target cell (cell expressing an antigen). The ADCC effect or the CDC effect may cause apoptosis. Such an effect of an antibody is specific to an antigen. That is to say, an antibody acts on cells expressing an antigen which the antibody recognizes regardless of whether the cells are cancer cells or normal cells. Therefore, the success in development of antibody therapeutic agents to cancers is dependent on discovery of antigens expressing in a cancer-specific manner and recognized by an antibody so as to cause the ADCC effect or the CDC effect. An antibody against to such an antigen is a promising candidate of a therapeutic agent capable of reliably killing target cancer cells while minimizing the influence (side effect) on normal cells.
In antibody drug development, it is essential to obtain antibodies that recognize “intact state” target cancer antigens existing on the surface of a cell membrane. However, since the target cancer antigen is membrane protein, it has been difficult to obtain an antibody against even known cancer antigen. In order to solve these problems, present inventors have produced a huge human antibody library including as many as 100 billion independent clones and established a comprehensive acquisition method for antibodies to proteins (cell surface antigens) existing on the surface of the cell membrane of cancer cells and tissues by using the library (patent documents 1 to 3).    [Patent document 1] WO01/062907    [Patent document 2] WO2001/096401    [Patent document 3] Japanese Patent Unexamined Publication No. 2005-185281    [Non-patent document 1] Mass R, et al.: The Concordance Between the Clinical Trials Assay (CTA) and Fluorescence in Situ Hybridization (FISH) in the Herceptin Pivotal Trials.: Proc Am Soci Clin Oncol 19, 75a, 2000    [Non-patent document 2] Berinstein N L, Grillo-Lopez A J, White C A, Bence-Bruckler I, Maloney D, Czuczman M, et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Annals of Oncology 1998, 9:995-1001.    [Non-patent document 3] Bruggemann M., Williams G. T., Bindon C. I., Clark M. R., Walker M. R., Jefferis R., Waldmann H., Neuberger M. S. (1987). Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J. Exp. Med., 166, 1351-1361.    [Non-patent document 4] Loos M. (1982). The classical complement pathway: mechanism of activation of the first component by antigen-antibody complexes. Prog. Allergy, 30, 135-192. Mol Immunol. 1982 May; 19 (5): 651-7.